The generation of B lymphocytes involves DNA breaks, recombination of variable (V), diversity (D) and joining (J) segments into the immunoglobulin variable region exons, somatic hypermutation and class switch recombination (1). Double strand DNA breaks are induced by the activity of the recombination activating proteins 1 and 2 (RAG1, RAG2) and are repaired by the non-homologous end joining pathway (NHEJ) (2). Guanosine-uracil mismatches are generated by activation-induced cytidine deaminase (AID) and are processed by the base excision repair pathway (BER) and the mismatch repair pathway (MMR) (3,4). These DNA lesions, if improperly repaired, may lead to genetic instability and chromosomal translocations in B lymphoid cells, and then to lymphomagenesis (5).
Diffuse large B-cell lymphoma (DLBCL) accounts for 30 to 40% of adult non-Hodgkin lymphomas (LNH). Most patients diagnosed with DLBCL achieve long-term remission after treatment, but a third of them relapse after conventional Rituximab (R)-based chemotherapy regimens such as combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) (6). DLBCL is a heterogeneous disease both in term of clinical and biological presentation (7). Gene expression profiling (GEP) of the tumors has allowed the identification of three molecular subgroups associated with distinct genetic abnormalities, clinical behavior and responsiveness to therapy (8-11).
The germinal-center B-cell-like (GCB) subgroup accounts for 50% of DLBCL, is associated with a good outcome and tumor cells have a GEP close to that healthy germinal-center B cells. The activated B cell-like subtype (ABC) subgroup accounts for 30% of cases, has a poorer outcome and tumor cells have a healthy peripheral blood activated B cell GEP with a nuclear factor kappa B (NF-kB) signature. Using CHOP-like chemotherapy, the 5-year overall survival rates of patients with GCB signature and of patients with ABC profile are 60% and 30% respectively (11). The third subtype, primary mediastinal B cell lymphoma (PMBL), accounts for 20% of cases, displays a mediastinal presentation and a GEP closed to that of Hodgkin's lymphoma, but with genes characteristic of mature B cells (10).
Distinct oncogenic pathways have been identified in DLBCL molecular subtypes as reviewed by Lenz et al (8). Some of them are linked with genomic instability as TP53 mutation, MDM2 gain or amplification, PTEN and ING1 deletion in the GCB subgroup or INK4A-ARF deletion in the ABC subgroup. Aberrant DNA repairs are likely a cause of DLBCL lymphomagenesis (12). Somatic and germline mutations in non Ig genes linked with the mismatch repair or non homologous end-joining pathways have been identified (12).
Tumorigenesis was described as a disease of DNA repair since it has at origin DNA mutations linked to genomic instability (13,14). Mutations of DNA repair genes were shown to be involved in cancer transformation (15-18). However, DNA repair pathways are required in cancer cells to survive to chronic replication stress that impede the duplication of their genome and could lead to mitotic catastrophe (19). DNA repair represents therefore a double-edged sword in cancer. To overcome this antagonism, tumor cells will become addicted to DNA repair pathways different from the defective one involved in the initial neoplastic transformation. This addiction could represent the Achilles' heel of tumor cells and can be exploited therapeutically to hamper repair of the intrinsic DNA damages occurring during replication or to amplify the chemotherapy induced DNA damages (19). Selective mutations of DNA repair genes including mismatch repair (MMR) genes (EXO1, MSH2 and MSH6), non homologous end-joining (NHEJ) genes (DCLRE11C, PRKDC, XRCC5 and XRCC6), homologous recombination (HR) BRCA2 gene and nucleotide excision repair DDB1 gene were reported in DLBCL (12). Furthermore, DLBCL high-risk patients overexpressed genes coding for nucleotide excision DNA repair (NER) pathway, including ERCC2/XPD, ERCC3/XPB, ERCC4/XPF, ERCC6/CSB, ERCC8/CSA, DDB2 and polymerase delta that could be linked with resistance to CHOP-based regimens (20,21).
In the present invention, the inventors aimed to identify deregulated DNA repair pathways in DLBCL tumor samples in order to exploit the concept of synthetic lethality. There is no disclosure in the art of a method of testing whether a patient suffering of diffuse large B-cell lymphoma will respond or not to a DNA repair pathway inhibitor selected from FANC, NER, BER, NHEJ, MMR and HRR DNA repair pathway inhibitors.